Solid pharmaceutical compositions containing pregabalin

ABSTRACT

A solid pharmaceutical composition containing pregabalin is described. The composition includes a matrix forming agent and a swelling agent and is suitable for once daily oral administration. Exemplary matrix forming agents include mixtures of polyvinyl acetate and polyvinylpyrrolidone, and exemplary swelling agents include cross-linked polymers of polyvinylpyrrolidone.

BACKGROUND OF THE INVENTION

This invention relates to solid pharmaceutical compositions containingpregabalin which are suitable for once daily (QD) oral dosing.

Pregabalin, or (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, binds tothe alpha-2-delta (α2δ) subunit of a calcium channel and is related tothe endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA),which is involved in the regulation of brain neuronal activity.Pregabalin exhibits anti-seizure activity, as discussed in U.S. Pat. No.5,563,175 to R. B. Silverman et al., and is useful for treating, amongother conditions, epilepsy, pain, physiological conditions associatedwith psychomotor stimulants, inflammation, gastrointestinal damage,alcoholism, insomnia, fibromyalgia, and various psychiatric disorders,including anxiety, depression, mania, and bipolar disorder. In theUnited States, pregabalin has been approved for the treatment ofdiabetic peripheral neuropathy, postherpetic neuralgia, and as anadjunctive treatment for partial onset seizures in adults. Pregabalin isavailable as an immediate release (IR) formulation in capsules and isadministered to patients two- or three-times daily (BID or TID).

Many patients receiving pregabalin or other drugs which are administeredtwo or more times daily would likely benefit from once daily dosing. Theconvenience of QD dosing generally improves patient compliance,especially for elderly patients and for patients taking multiplemedications. Once per day dosing may also lessen or prevent potentiallyundesirable dose-related effects by reducing peak blood levels (C_(MAX))and may also increase drug efficacy by increasing minimum plasmaconcentrations (C_(MIN)).

Once daily dosing of pregabalin, however, presents numerous challenges.Conventional extended release (ER) compositions are problematic for QDdosing because pregabalin is not absorbed uniformly in thegastrointestinal (GI) tract. Clinical studies indicate that pregabalinis absorbed in the small intestine and the ascending colon in humans,but is poorly absorbed beyond the hepatic flexure. This suggests thatthe mean absorption window for pregabalin is, on average, about sixhours or less—any drug release from a conventional ER dosage form beyondsix hours would thus be wasted because the dosage form has traveledbeyond the hepatic flexure. Furthermore, pregabalin is a γ-amino acidwhich under normal storage conditions may undergo intramolecularcyclization to form a lactam, 4-isobutyl-pyrrolidin-2-one. See, e.g., WO99/10186 and WO 99/59573, both to A. Aomatsu. Although it is known thatthe non-active components of the pharmaceutical composition may affectlactam formation, it is difficult to predict which excipients may leadto undesirable lactam formation.

SUMMARY OF THE INVENTION

The present invention provides a stable pharmaceutical compositioncontaining pregabalin that is useful for once daily oral dosing. Whenadministered as a solid dosage form, such as a tablet, thepharmaceutical composition is retained in the stomach for a longerperiod of time than an IR dosage form. While it is retained in thestomach, the pharmaceutical composition continuously releasespregabalin. Eventually, the pharmaceutical composition passes out of thestomach and into the small intestine where it may continue to releasepregabalin. Extending the period of time during which pregabalin isreleased in the stomach effectively widens the absorption windowassociated with IR dosing, thereby permitting QD dosing. Furthermore,stability studies suggest that none of the components of thepharmaceutical composition promote undesirable lactam formation.

One aspect of the invention provides a pharmaceutical composition whichis suitable for QD dosing and includes an active pharmaceuticalingredient and excipients. The active pharmaceutical ingredient includespregabalin, or a pharmaceutically acceptable complex, salt, solvate orhydrate of pregabalin, and the excipients include a matrix forming agentand a swelling agent. The matrix forming agent includes polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP), and the swelling agentincludes cross-linked polyvinylpyrrolidone. The active pharmaceuticalingredient typically comprises from about 5% to about 60% of thepharmaceutical composition by weight; the matrix forming agent typicallycomprises from about 5% to about 45% of the pharmaceutical compositionby weight, and the swelling agent typically comprises from about 5% toabout 70% of the pharmaceutical composition by weight.

A further aspect of the invention provides a solid dosage form, such asa tablet, which is adapted for once daily oral dosing. The solid dosageform comprises the pharmaceutical composition described above. Uponcontact with water, which is present, for example, in the gastric fluidof humans, the dosage form swells or expands to a size of about 9 mm orgreater.

An additional aspect of the invention provides a method of treating acondition or disorder in a subject that is responsive to pregabalin. Themethod includes orally administering to the subject once per day thepharmaceutical composition described above.

Another aspect of the invention provides a method of treating acondition or disorder in a subject that is responsive to pregabalin, themethod comprising orally administering to the subject a pharmaceuticalcomposition once daily. The pharmaceutical composition comprisespregabalin and one or more excipients. The composition is adapted toprovide the subject in any 24-hour period with a single steady-statemaximum pregabalin concentration of 9 μg/mL or less and a steady-stateminimum pregabalin concentration of about 0.7 μg/mL or greater.

DETAILED DESCRIPTION Definitions and Abbreviations

Unless otherwise indicated, this disclosure uses the followingdefinitions.

“About,” “approximately,” and the like, when used in connection with anumerical variable, generally refers to the value of the variable and toall values of the variable that are within the experimental error (e.g.,within the 95% confidence interval for the mean) or within ±10% of theindicated value, whichever is greater.

“Subject” refers to a mammal, including a human.

“Pharmaceutically acceptable” substances refers to those substanceswhich are within the scope of sound medical judgment suitable for use incontact with the tissues of subjects without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit-to-risk ratio, and effective for their intended use.

“Treating” generally refers to reversing, alleviating, inhibiting theprogress of, or preventing a disorder or condition in a subject, or topreventing one or more symptoms of such disorder or condition in thesubject.

“Treatment” refers to the act of “treating” as defined immediatelyabove.

“Drug,” “drug substance,” “active pharmaceutical ingredient,” and thelike, refer to a compound (e.g., pregabalin) that may be used fortreating a subject in need of treatment.

“Therapeutically effective amount” of a drug refers to the quantity ofthe drug that may be used for treating a subject and is generally in therange of about 0.001 to about 100 mg/kg/day for an adult, and is oftenin the range of about 0.1 to about 50 mg/kg/day for an adult. For anadult human, a typical daily dose of a drug is in the range of about 1mg to about 1000 mg. For pregabalin, the daily dose for an adult humanmay be in the range of about 50 mg to about 1800 mg and is often in therange of about 50 mg to about 900 mg.

“Inert” substances refer to those substances that may influence thebioavailability of the drug, but are otherwise pharmaceuticallyinactive.

“Excipient” or “adjuvant” refers to any inert substance.

“Pharmaceutical composition” refers to the combination of one or moredrug substances and one or more excipients.

“Drug product,” “pharmaceutical dosage form,” “dosage form,” “finaldosage form” and the like, refer to a pharmaceutical composition that isadministered to a subject in need of treatment and generally may be inthe form of tablets, capsules, sachets containing powder or granules,liquid solutions or suspensions, patches, and the like.

“Solvate” describes a molecular complex comprising the drug substance(e.g., pregabalin) and a stoichiometric or non-stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules (e.g.,ethanol). When the solvent is tightly bound to the drug the resultingcomplex will have a well-defined stoichiometry that is independent ofhumidity. However, when the solvent is weakly bound, as in channelsolvates and hygroscopic compounds, the solvent content will bedependent on humidity and drying conditions. In such cases, the complexwill often be non-stoichiometric.

“Hydrate” describes a solvate comprising the drug substance and astoichiometric or non-stoichiometric amount of water.

“Retained in the stomach,” when used in connection with a pharmaceuticalcomposition or dosage form, means that at least a portion of the dosageform remains in a subject's stomach following oral administration forabout three or more hours, which is substantially longer than theaverage residence time of a corresponding IR dosage form. While it isretained in the stomach, the dosage form continuously releases the drug.

“Release,” “released,” and the like, when used in connection with apharmaceutical composition or dosage form, refers to the portion of thedrug substance that leaves the dosage form following contact with anaqueous environment. Unless otherwise indicated, the quantity of drugreleased from a dosage form is measured by dissolution testing in water(37° C., initial pH of 6.8, using apparatus 2) as described the UnitedStates Pharmacopeia, 28th Revision, Chapter 711, Second Supplement,(Aug. 1, 2005 to Dec. 31, 2005). The results of the dissolution testingare reported as % (w/w) released as a function of time or as the releasetime, t_(N), where N is the % (w/w) of drug released or dissolved. Forthe purposes of this disclosure, complete drug release occurs when atleast 90% of the drug has been released from the dosage form (i.e., att₉₀).

“Steady-state,” when used in connection with pharmacokinetic (PK)parameters such as the minimum (C_(MIN)) and maximum (C_(MAX))concentrations of the drug substance in the blood plasma of the subject,refers to the approximately constant values of the PK parameters thatresult from repeated administration of a dosage form at uniform dosingintervals. For dosage forms containing pregabalin, steady-state valuesof C_(MAX) and C_(MIN) usually occur about 24 to 48 hours followingfirst administration.

A test dosage form is “bioequivalent” to a reference dosage form if the90% confidence interval estimate for the ratio of the mean value of thetotal exposure from treatment with the test dosage form to the meanvalue of the total exposure from treatment with the reference dosageform lies within the range of 80% to 125%. Here, the ratio is expressedas a percentage (100% x test/reference) and the 90% confidence intervalis expressed as a percentage of the reference mean. For single-dosestudies, the total exposure is the area under the plasmaconcentration-time curve from time zero (time of dosing) to timeinfinity; for steady-state studies, the total exposure is the area underthe plasma concentration-time curve over the dosing interval. See, U.S.Department of Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research, Guidance for Industry,Bioavailability and Bioequivalence Studies for Orally Administered DrugProducts—General Considerations (Rev. 1, March 2003).

“Poorly soluble” substances are those that are classified as “sparinglysoluble,” “slightly soluble,” “very slightly soluble,” or “practicallyinsoluble,” i.e., compounds having a solubility of one part of water toabout 30-100 parts of water, about 100-1000 parts of water, about1000-10,000 parts of water, or about 10,000 or greater parts of water,respectively, when measured at room temperature and a pH of 5 to 7.

TABLE 1 lists abbreviations used throughout the specification.

TABLE 1 List of Abbreviations Abbreviation Description ACN acetonitrileAPI active pharmaceutical ingredient aq aqueous BID twice daily CAPcellulose acetate phthalate CAT cellulose acetate trimellitate CECcarboxyethylcellulose CMC carboxymethylcellulose CMECcarboxymethylethylcellulose C_(MAX) maximum concentration of API insubject's plasma C_(MIN) minimum concentration of API in subject'splasma dpm dips per minute EC ethyl cellulose ER extended release Et₃Ntriethylamine GABA γ-aminobutyric acid GI gastrointestinal HDPE highdensity polyethylene HEC hydroxyethyl cellulose HPChydroxypropylcellulose HPCAP hydroxypropylcellulose acetate phthalateHPCAS hydroxypropylcellulose acetate succinate HPLC high-pressure liquidchromatography HPMC hydroxypropylmethylcellulose HPMCAPhydroxypropylmethylcellulose acetate phthalate HPMCAShydroxypropylmethylcellulose acetate succinate HPMCAThydroxypropylmethylcellulose acetate trimellitate HPMCPhydroxypropylmethylcellulose phthalate IR Immediate release kp kilopondsL, W, H, V length, width, height, volume MC methylcellulose Me methyl Mnnumber average molecular weight Mv molecular weight based on intrinsicviscosity Mw weight average molecular weight n number of samples PEpolyethylene PEG polyethylene glycol PPG polypropylene glycol PKpharmacokinetic PVA polyvinyl alcohol PVAc polyvinyl acetate PVPpolyvinylpyrrolidone PVPP polyvinylpolypyrrolidone QD once daily RHrelative humidity rpm revolutions per minute RT room temperature, about20° C. to 25° C. s seconds t_(R) dosage form retention time in subject'sstomach t_(N) dosage form drug release (aqueous dissolution) time, whereN is % released; N ≧ 90 corresponds to complete release t_(MAX) time toreach C_(MAX) following administration TID three times daily USP UnitedStates Pharmacopoeia VA vinylacetate v/v volume/total volume × 100, %w/v weight (g)/total volume (mL) × 100, % w/w weight (mass)/total weight(mass) × 100, %

Any reference in this disclosure to a temperature range, a pH range, aweight (mass) range, a molecular weight range, a percent range, etc.,whether expressly using the words “range” or “ranges,” includes theindicated endpoints and points between the end points.

As noted above, the peroral pharmaceutical composition comprises anactive pharmaceutical ingredient (API) and excipients. The activepharmaceutical ingredient includes pregabalin or a pharmaceuticallyacceptable complex, salt, solvate or hydrate thereof. The API generallycomprises from about 5% to about 60% of the pharmaceutical compositionby weight, which would typically correspond to a solid dosage form(e.g., tablet) that contains from about 50 mg to about 600 mg ofpregabalin. Besides pregabalin, other useful active pharmaceuticalingredients may include those having a similar half-life (e.g., about 9hours or less) and absorption characteristics in the GI tract.

Pregabalin may be prepared using known methods. In some of thesemethods, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid issynthesized and subsequently resolved into its R- and S-enantiomers.Such methods are described in U.S. Pat. No. 5,563,175 to R. B. Silvermanet al., U.S. Pat. No. 6,046,353 to T. M. Grote et al., U.S. Pat. No.5,840,956 to T. M. Grote et al., U.S. Pat. No. 5,637,767 to T. M. Groteet al., U.S. Pat. No. 5,629,447 to B. K. Huckabee & D. M. Sobieray, andU.S. Pat. No. 5,616,793 to B. K. Huckabee & D. M. Sobieray. In each ofthese methods, the racemate is reacted with a chiral acid (a resolvingagent) to form a pair of diastereoisomeric salts, which are separated byknown techniques, such as fractional crystallization and chromatography.In other methods, pregabalin is synthesized directly using a chiralauxiliary, (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. See, e.g., U.S.Pat. Nos. 6,359,169, 6,028,214, 5,847,151, 5,710,304, 5,684,189,5,608,090, and 5,599,973, all to Silverman et al. In another method,pregabalin is prepared via asymmetric hydrogenation of acyano-substituted olefin to produce a chiral cyano precursor of(S)-3-aminomethyl-5-methyl hexanoic acid, which is subsequently reducedto yield pregabalin. See U.S. Patent Application 2003/0212290 A1 to Burket al.

The pharmaceutical composition may employ any pharmaceuticallyacceptable form of pregabalin, including its free form (zwitterion), andits pharmaceutically acceptable complexes, salts, solvates, hydrates,and polymorphs. Salts include, without limitation, acid addition saltsand base addition salts, including hemisalts. Pharmaceuticallyacceptable acid addition salts may include nontoxic salts derived frominorganic acids such as hydrochloric, nitric, phosphoric, sulfuric,hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, aswell nontoxic salts derived from organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic andaromatic sulfonic acids, etc. Potentially useful salts include acetate,aspartate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,besylate, bicarbonate, carbonate, bisulfate, sulfate, pyrosulfate,bisulfite, sulfite, borate, camsylate, caprylate, citrate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide,bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate,maleate, malonate, mandelate, mesylate, methylsulfate, naphthylate,2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate,pyrophosphate, phthalate, propionate, saccharate, sebacate, stearate,suberate, succinate, tartrate, tosylate, trifluoroacetate, and the like.

Pharmaceutically acceptable base salts may include nontoxic saltsderived from bases, including metal cations, such as an alkali oralkaline earth metal cation, as well as amines. Examples of potentiallyuseful salts include, without limitation, aluminum, arginine,N,N′-dibenzylethylenediamine, calcium, chloroprocaine, choline,diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine,glycine, lysine, magnesium, N-methylglucamine, olamine, potassium,procaine, sodium, tromethamine, zinc, and the like. For a discussion ofuseful acid and base addition salts, see S. M. Berge et al., J. ofPharm. Sci., 66:1-19 (1977); see also Stahl and Wermuth, Handbook ofPharmaceutical Salts: Properties, Selection, and Use (2002).

The pharmaceutically acceptable salts of pregabalin may be prepared byreacting its free (or zwitterionic) form with a desired acid or base; byremoving an acid- or base-labile protecting group from a suitableprecursor of pregabalin; by ring-opening a suitable cyclic (lactam)precursor using a desired acid or base; or by converting one salt ofpregabalin to another by reaction with an appropriate acid or base or bycontact with a suitable ion exchange column. All of thesetransformations are typically carried out in a solvent. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionized to almost non-ionized.

Pregabalin may exist in unsolvated and solvated forms (includinghydrates) and in the form of other multi-component complexes in whichthe drug and at least one additional component is present instoichiometric or non-stoichiometric amounts. Multi-component complexes(other than salts and solvates) include clathrates (drug-host inclusioncomplexes) and pharmaceutical co-crystals. The latter are defined ascrystalline complexes of neutral molecular constituents that are boundtogether through non-covalent interactions. Co-crystals may be preparedby melt crystallization, by recrystallization from solvents, or byphysically grinding the components together. See, e.g., O. Almarsson &M. J. Zaworotko, Chem. Comm. 1889-1896 (2004). For a general review ofmulti-component complexes, see J. K. Haleblian, J. Pharm. Sci.64(8):1269-88 (1975).

Useful forms of pregabalin include all of its polymorphs and crystalhabits, the corresponding R-enantiomer of pregabalin, and variousmixtures of pregabalin and the R-enantiomer, including a racemic mixtureof pregabalin and the R-enantiomer.

In addition, the pharmaceutical composition may employ prodrugs ofpregabalin. Such prodrugs may be prepared by replacing appropriatefunctional groups of pregabalin with functionalities known as“pro-moieties,” as described, for example, in H. Bundgaar, Design ofProdrugs (1985). Examples of prodrugs would thus include derivatives ofpregabalin in which an ester group replaces the carboxylic acid group oran amide group replaces the amino group.

Useful forms of pregabalin may also include pharmaceutically acceptableisotopically labeled compounds in which one or more atoms are replacedby atoms having the same atomic number, but an atomic mass or massnumber different from the atomic mass or mass number that predominatesin nature. Examples of isotopes suitable for inclusion in pregabalininclude isotopes of hydrogen (²H and ³H), carbon (¹¹C, ¹³C and ¹⁴C), andnitrogen (¹³N and ¹⁵N). Isotopically labeled forms of pregabalin maygenerally be prepared by techniques known to those skilled in the art.

In addition to the API, the pharmaceutical composition includes variousexcipients, including a matrix forming agent and a swelling agent. Forperoral solid dosage forms (e.g., tablets), the matrix forming agentimparts structural integrity and helps control or extend the rate ofdrug release, among other functions. The matrix forming agent maycomprise about 5% to about 45% of the pharmaceutical composition byweight and often comprises about 20% to about 35% of the pharmaceuticalcomposition by weight.

Useful matrix forming agents include physical mixtures of polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone(PVP), which is also known as povidone or povidonum, is a homopolymer of1-vinyl-pyrrolidin-2-one, typically having a molecular weight (Mw) ofabout 1×10³ to about 1×10⁷, about 2.5×10³ to about 3×10⁶, or about 1×10⁴to about 1×10⁵. Polyvinylpyrrolidone is available from BASF under thetrade name KOLLIDON® and from ISP under the trade name PLASDONE®.Polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, typicallyhaving a molecular weight (Mw) of about 1×10⁵ to about 1×10⁶. Based onthe total weight of PVAc and PVP, the matrix forming agent may comprisefrom about 0% to about 90% PVAc by weight, from about 20% to about 90%PVAc by weight, from about 40% to about 90% PVAc by weight, from about60% to about 90% PVAc by weight, from about 70% to about 90% PVAc byweight, or from about 80% to about 90% PVAc by weight. In many cases,the matrix forming agent comprises from about 70% to about 85% PVAc byweight, based on the total weight of PVAc and PVP. A useful matrixforming agent is available from BASF under the trade name KOLLIDON® SR,which is nominally an 80/19 (w/w) mixture of mixture of PVAc and PVP,respectively.

The pharmaceutical composition includes other excipients, including aswelling agent. As its name suggests, the swelling agent absorbs waterfrom the gastric fluid which causes the solid dosage form to expand insize, and may also influence the drug release rate by, for example,creating channels or by forming a hydrocolloid. Swelling agents may besoluble or insoluble in water. The swelling agent may comprise about 5%to about 70% of the pharmaceutical composition by weight, about 10% toabout 70% of the pharmaceutical composition by weight, or about 15% toabout 70% of the pharmaceutical composition by weight. In many cases,the swelling agent may comprise about 10% to about 55% of thepharmaceutical composition by weight, about 20% to about 55% of thepharmaceutical composition by weight, or about 30% to about 55% of thepharmaceutical composition by weight.

Useful swelling agents include cross-linked homopolymers of1-vinyl-pyrrolidin-2-one, which are known as crospovidone,crospovidonum, cross-linked povidone, and polyvinylpolypyrrolidone(PVPP). Crospovidones, which are insoluble in water, are available fromBASF under the trade names KOLLIDON® CL and KOLLIDON® CL-10 and from ISPunder the trade names POLYPLASDONE® XL and POLYPLASDONE® XL-10.

In addition to crospovidones, the swelling agent may includepolyethylene oxide (PEO), which is also known as polyoxirane andpolyoxyethylene. Polyethylene oxides are homopolymers of ethylene oxide,typically having a molecular weight (Mw) of about 1×10⁵ to about 1×10⁷or about 1×10⁶ to about 1×10⁷. Polyethylene oxides are supplied invarious grades based on molecular weight and are commercially availablefrom Union Carbide under the trade name POLYOX®. When used inconjunction with a crospovidone, the PEO typically comprises from about5% to about 35% or from about 10% to about 25% of the pharmaceuticalcomposition by weight, and the crospovidone typically comprises fromabout 10% to about 35% or from about 20% to about 30% of thepharmaceutical composition by weight.

In addition to a matrix forming agent and a swelling agent, thepharmaceutical composition may optionally include a gelling agent, whichmodifies (e.g. extends) the drug release characteristics of the dosageform. Gelling agents, which are also known as hydrocolloids, includesynthetic and naturally occurring polymers that are typically poorlysoluble (e.g., slightly soluble to sparingly soluble) in water. Whenexposed to water, the gelling agent forms a viscous mixture (i.e.,viscosity greater than water) that retards diffusion of the drug throughthe dosage form thereby extending the time for drug release from thedosage form. The gelling agent typically comprises from about 0% toabout 25%, from about 5% to about 25%, or from about 5% to about 20% ofthe pharmaceutical composition based on weight. Useful gelling agentsinclude carbomers, polysaccharides or both.

Carbomers are acrylic acid polymers which are cross-linked withallylsucrose or allyl ethers of penaerythritol and are known variouslyas carboxy polymethylene, polyacrylic acid, and carboxyvinyl polymers.Carbomers have from about 56% to about 68% carboxy moieties on a drybasis and have number-average molecular weights of about 1×10⁵ to about1×10¹⁰ or about 7×10⁵ to about 4×10⁹. Carbomers are available from RITAunder the trade name ACRITAMER® and from Noveon under the trade namesCARBOPOL® and PEMULEN®.

Representative polysaccharides include xanthan gum, inulin, guar gum,chitosan, ceratonia, and carregeenan, either alone or in combination.Xanthan gum, which is also known as corn sugar gum, is a polysaccharidehaving a molecular weight (Mw) of about 2×10⁶. The polymer is comprisedof a primary chain of β-D-glucose moieties linked by (1→4) glycosidicbonds, as well as trisaccharide side chains, which are attached toalternating glucopyranose moieties. Each of the side chains is comprisedof a β-D-glucuronic acid moiety which is linked to a β-D-mannose moietyand an α-D-mannose moiety via (1→4) and (1→2) glycosidic bonds,respectively. The α-D-mannose moiety is linked to the primary chain viaa (1→3) glycosidic bond and a majority of the terminal β-D-mannosemoieties are linked to pyruvate moieties. Xanthan gum is typicallyprepared as a sodium, potassium, or calcium salt, and is available invarious grades having different particle sizes from CP Kelco under thetrade names KELTROL® and XANTURAL®, from Rhodia under the trade nameRHODIGEL®, and from R.T. Vanderbilt Company, Inc. under the trade nameVANZAN®.

Inulin, which is also known as oligofructose and polyfructose, is aclass of naturally occurring polysaccharides comprised of a linear chainof β-D-fructose moieties linked by (2→1) glycosidic bonds, which isusually terminated with a glucose molecule. The number of D-fructosemoieties may range from 2 to about 140, but typically ranges from about25 to about 30. Inulins are available from Sensus Operations CV underthe trade name FRUTAFIT®.

Guar gum, which is also known as guar galactomannan, guar flour, andjaguar gum, is a hydrocolloidal polysaccharide having a molecular weight(Mw) of about 2×10⁵. Guar gum is comprised of a linear chain ofβ-D-mannose moieties linked by (1→4) glycosidic bonds and havingmonosaccharide side chains comprised of α-D-galactose moieties linked tothe glucopyranose moieties by (16) glycosidic bonds. The ratio ofβ-D-mannose moieties to α-D-galactose moieties generally ranges fromabout 1:1.4 to about 1:2 and the number-average molecular weight istypically about 2×10⁵. Guar gun is obtained from natural sources, butsynthetic derivatives are also available, including guar acetate, guarphthalate, guar acetate phthalate, oxidized guar gum, and sodiumcarboxymethyl guar. Guar gum is available in various particles sizesfrom Aqualon under the trade name GALACTASOL® and from Danisco under thetrade names MEYPRO® Guar and MEYPRODOR.

Chitosan is known by a variety of names including chitosanhydrochloride, chitosani hydrochloridum, deacetylated chitin,deactylchitin, poly-β-(1,4)-2-amino-2-deoxy-D-glucose,2-amino-2-deoxy-(1,4)-β-D-glucopyranan, β-1,4-poly-D-glucosamine,poly-D-glucosamine, and poly-(1,4-β-D-glucopyranosamine). Chitosan is aclass of sparingly water-soluble polysaccharides comprised of copolymersof β-D-glucosamine and N-acetyl-β-D-glucosamine, which are prepared bydeacetylation and depolymerization of chitin. The extent ofdeacetylation and depolymerization varies from manufacturer, butdeacetylation of about 80% or greater and number-average molecularweights of about 1×10⁴ to about 1×10⁶ are typical.

Ceratonia is a naturally occurring polysaccharide which is also known ascarob bean gum, carob flour, ceratonia gum, Cheshire gum, locust beangum, and St. John's bread. Like guar gum, ceratonia is a galactomannan.It is comprised of a primary chain of β-D-mannose moieties linked by(1→4) glycosidic bonds and includes side chains comprised of singleβ-D-galactose moieties which are linked to every fourth or fifthD-mannopyranose moiety by (1→6) glycosidic bonds. The molecular weight(Mw) of Ceratonia may range from about 5×10⁴ to about 3×10⁶ and isavailable in various particle sizes from Danisco under the trade namesGRINDSTED®LBG and MEYPRO® LBG.

Carregeenan, which is also known as Chondrus extract and Irish mossextract, is a hydrocolloid polysaccharide comprised primarily ofpotassium, sodium, calcium, magnesium, or ammonium sulfate esters ofD-galactose and 3,6-anhydro-D-galactose copolymers. The pyranosemoieties are linked by alternating α (1→3) and β (1→4) glycosidic bonds.There exist at least three types of carregeenan, known as λ-carrageenan,ι-carrageenan, and κ-carrageenan, which differ in the amounts of sulfateester and 3,6-anhydrogalactopyranose moieties. Lambda-carrageenan is anon-gelling polymer which contains about 35% sulfate ester groups byweight and no 3,6-anhydrogalactose moieties; ι-carrageenan is a gellingpolymer which contains about 32% sulfate ester groups by weight andabout 30% 3,6-anhydrogalactose moieties; and κ-carrageenan is acomparatively stronger (i.e., inelastic, brittle or firm) gellingpolymer which contains about 25% sulfate ester moieties by weight andabout 34% 3,6-anhydrogalactose moieties. Carrageenan is available in anumber of grades based on gelling type, aqueous solubility, andviscosity when blended with water and can be obtained from FMCCorporation under the trade names GELCARIN®, VISCARIN® and SEASPEN®.

Other useful polysaccharides include cellulosic derivatives whichexhibit aqueous solubility over at least a portion of the pH range of 1to 8, inclusive. Useful polymers thus include ionizable and nonionizablecellulosic polymers, including those having ether or ester or ether andester substituents and copolymers thereof, including so-called “enteric”and “non-enteric” polymers.

Exemplary ionic cellulosic polymers include carboxymethylcellulose (CMC)and its sodium or calcium salts; carboxyethylcellulose (CEC);carboxymethylethylcellulose (CMEC); hydroxyethylmethylcellulose acetatephthalate; hydroxyethylmethylcellulose acetate succinate;hydroxypropylmethylcellulose phthalate (HPMCP);hydroxypropylmethylcellulose succinate; hydroxypropylcellulose acetatephthalate (HPCAP); hydroxypropylcellulose acetate succinate (HPCAS);hydroxypropylmethylcellulose acetate phthalate (HPMCAP);hydroxypropylmethylcellulose acetate succinate (HPMCAS);hydroxypropylmethylcellulose acetate trimellitate (HPMCAT);hydroxypropylcellulose butyrate phthalate; carboxymethylethylcelluloseand its sodium salt; cellulose acetate phthalate (CAP); methylcelluloseacetate phthalate; cellulose acetate trimellitate (CAT); celluloseacetate terephthalate; cellulose acetate isophthalate; cellulosepropionate phthalate; cellulose propionate trimellitate; cellulosebutyrate trimellitate; and mixtures thereof. The ionic cellulosicpolymers are available from numerous commercial suppliers. For example,sodium CMC may be obtained from Hercules under the trade names AQUALON®and BLONASE® in various grades based on particle size and degree (e.g.,about 0.7 to about 1.2) of carboxymethyl-substitution of theanhydroglucose units.

Exemplary nonionic cellulosics include methylcellulose (MC); ethylcellulose (EC); hydroxyethyl cellulose (HEC); hydroxypropylcellulose(HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropylmethylcelluloseacetate; hydroxyethylmethylcellulose; hydroxyethylcellulose acetate;hydroxyethylethylcellulose; and mixtures thereof. The nonioniccellulosics are available from a variety of commercial sources. Forexample, MC may be obtained from the Dow Chemical Company under thetrade name METHOCEL® A, which has about 27.5% to about 31.5% methoxygroups per anhydroglucose unit based on weight; HPC may be obtained fromHercules under the trade name KLUCEL® in various grades (e.g., EF, EXF,LF, JF, GF, MF, HF, and HXF) having molecular weights ranging from about8×10⁴ to about 1.2×10⁶ (Mw); HEC may be obtained from Hercules under thetrade name NATROSOL® 250 in various grades (e.g., L, G, M, H, H, andHHX) having molecular weights ranging from about 9×10⁴ to about 1.3×10⁶(Mv); HPMC may be obtained from Hercules under the trade name BENECEL®in various grades (e.g., MP 843, MP 814, MP 824, MP 844, and MP 874)based on aqueous viscosity and from the DOW Chemical Company under tradename METHOCEL®, in various grades (e.g., E, F, J, K and 310) havingabout 18% to about 29% and about 5% to about 27% methoxy and2-hydroxypropoxy groups per anhydroglucose unit based on weight,respectively.

The pharmaceutical composition may optionally include one or morelubricants, which aid in various processing steps including componentblending and tableting. When present, the lubricants typically comprisefrom about 0.5% to about 2% of the pharmaceutical composition based onweight. Representative lubricants include talc, stearic acid and itsmetal salts, including calcium stearate, magnesium stearate, and zincstearate; stearic acid esters, including polyoxyethylene stearate,glyceryl monostearate, glyceryl palmitostearate, and the like; glycerylbehenate (e.g., COMPRITOL®, which is available from Gattefosse Inc.),sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil,poloxamers (copolymers of ethylene oxide and propylene oxide),polyethylene glycol, sodium chloride, and mixtures thereof.

The pharmaceutical composition may include other excipients, suchdiluents or fillers, which comprise from about 0% to about 30% of thecomposition by weight. Diluents may improve the flow characteristics ofthe pharmaceutical composition during component blending and tabletingand may enhance the physical properties of tablets, providing, forexample, increased compression strength or hardness, decreasedfriability, and so on. Representative diluents include monosaccharides,disaccharides, polyhydric alcohols, and mixtures thereof, such asdextrose, lactose monohydrate, spray-dried lactose monohydrate,anhydrous lactose, sucrose, mannitol, spray-dried mannitol, xylitol, andsorbitol. Other useful diluents may include microcrystalline cellulose,starch, pregelatinized starch, dihydrous calcium phosphate, anhydrousdicalcium phosphate, and mixtures thereof.

To prepare the drug product, the components of the pharmaceuticalcomposition are typically dry blended using, e.g., a v-cone blender. Theresulting mixture is subsequently compacted in a press to yieldindividual (unit) dosages (tablets). To improve product homogeneity, thecomponents may be combined and blended in stages. For example, the APImay be granulated with one or more of the components by, e.g., fluid bedor extrusion granulation, and then blended with the remainingcomponents. Similarly, the API may be first dry blended with one or morematrix forming agents, while other excipients, such as swelling agents,gelling agents, diluents, lubricants, and the like, may be subsequentlyadmixed in one or more blending operations. If desired, prior toblending one or more of the components may be sized by screening ormilling or both. To prepare the final drug product, the compresseddosage forms may undergo further processing, such as polishing, coating,and the like. For a discussion of dry blending, wet and dry granulation,milling, screening, tableting, coating, and the like, as well as adescription of alternative techniques for preparing drug products, seeA. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy(20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical DosageForms: Tablets, Vol. 1-3 (2d ed., 1990); and D. K. Parikh & C. K.Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81(1997).

The pharmaceutical composition is ingested whole and begins to swell orexpand when it contacts the gastric fluid (water) in the subject'sstomach. The dosage form may have any shape, and includes disk- oroval-shaped tablets defined by a pair of circular or elliptical convexor planar surfaces which are connected by a continuous, substantiallyflat lateral surface; polygonal-shaped (e.g., triangular, quadrangular,pentagonal, hexagonal, etc.) tablets which have rounded corners andedges and are defined by a pair of convex or planar multi-sided surfaces(e.g., triangles, quadrilaterals, pentagons, hexagons, etc.) that areconnected by substantially flat lateral surfaces; and cylindrical-shapedtablets having hemispherical or hemispheroidal ends and having circularor elliptical cross-sections.

The QD dosage form may be retained in the stomach by size exclusion, bydosing with a meal, by dosing before bedtime, or by some combination ofthese mechanisms. For retention via size exclusion alone, the dosageform expands to a size that prevents it from exiting the stomach throughthe pylorus. Since the average diameter of the pylorus in an adult isabout 13 mm, the size of the dosage form following expansion would rangefrom about 13 mm to about 20 mm or larger, from about 15 mm to about 20mm or larger, or from about 17 mm to about 20 mm or larger. Here, the“size” of the dosage form corresponds to the largest linear dimension ofa cross-section of the dosage form having the smallest area. Forexample, the size of a disk-shaped tablet corresponds to its diameterand the size of a cylindrical-shaped tablet corresponds to the diameterof its circular cross-section or to the long axis of its ellipticalcross-section.

To achieve QD dosing, the dosage form is retained in the stomach forseveral hours (e.g., t_(R)≧3, 4, 5 or 6 hours) and releases pregabalinover an extended period of time (e.g., t₉₀>10, 11, 12, 13, 14, 15, 16,17, 18, 19 or 20 hours). The dosage form is typically retained in thesubject's stomach for a period of time that ranges from about 3 hours toabout 11 hours (3≦t_(R)≦11), from about 6 hours to about 14 hours(6≦t_(R)≦14), or from about 8 hours to about 14 hours (8≦t_(R)≦14), andit releases pregabalin over a period of time that ranges from about 12hours to about 16 hours (12≦t₉₀≦16), from about 12 hours to about 18hours (12≦t₉₀≦18), from about 12 hours to about 20 hours (12≦t₉₀≦20),from about 14 hours to about 20 hours (14≦t₉₀≦20), or from about 16hours to about 20 hours (16≦t₉₀≦20). As described in the PK simulationsin the Examples below, QD dosage forms that release pregabalin over aperiod of time that is about 4 hours to about 6 hours longer than thetime the dosage form is retained in the stomach appear to minimizevariability among patients.

Because eating delays gastric emptying and sleeping decreases GImotility, the dosage form may be administered once daily after a meal orbefore bedtime (e.g., within about one hour of sleep). To take advantageof both effects and to further prolong drug release, the QD dosage formmay be taken after the last meal before bedtime (e.g., after an eveningmeal). For QD dosage forms taken with a meal or taken before bedtime ortaken with a meal and before bedtime, the dosage form may be retained inthe stomach with little or no size expansion. In such cases, forexample, the size of the dosage form following expansion may be about 9mm or more.

During any 24-hour period, the QD dosage form achieves a steady-stateC_(MAX) that is about equal to or less than the steady-state C_(MAX) ofa corresponding immediate release formulation of the API that is takentwo- or three-times daily. Likewise, the QD formulation ideally achievesa steady-state C_(MIN) that is about equal to or greater than thesteady-state C_(MIN) of the IR formulation that is taken two- orthree-times daily. An IR formulation containing 300 mg of pregabalin,which is taken twice daily, exhibits an average steady-state C_(MAX) ofabout 8.9 μg/mL and an average steady-state C_(MIN) of about 2.8 μg/mL,and an IR formulation containing 150 mg of pregabalin, which is takentwice daily, exhibits an average steady-state C_(MAX) of about 4.4 μg/mLand an average steady-state C_(MIN) of about 1.4 μg/mL. A QD formulationcontaining pregabalin would ideally achieve an average steady stateC_(MAX) of about 9 μg/mL or less and an average steady-state C_(MIN) ofabout 0.7 μg/mL or greater.

EXAMPLES

The following examples are intended to be illustrative and non-limiting.Unless otherwise indicated, the following procedures are used to measuredrug release (aqueous dissolution), swelling, rigidity, and stability ofthe drug product as a function of time.

Drug Product Dissolution

The amount of API released from drug product samples immersed in aqueousdissolution media (0.06 N HCl or 0.5 M acetate buffer) at 37° C. ismeasured using a USP Apparatus 2 (paddles) or Apparatus 3 (reciprocatingcylinder), which are operated at 50 rpm or 5 dpm, respectively. Samplesof the dissolution media (1 mL) are typically taken at 1, 2, 4, 6, 9,12, 16, and 24 hours and are analyzed using HPLC under the followingconditions: column: Zorbax SB-CN, 150 mm×4.6 mm, 5 μm particle size;column temperature: 23° C.; detector wavelength: 210 nm; flow rate 1mL/min; injection volume: 25 μL; mobile phase composition: 0.05 Msulfonic acid/hexane and 2 mL Et₃N; pH adjusted to 3.1 withorthophosphoric acid:ACN (880:130); run time: 8 min.

Drug Product Swelling

The increase in the size of the drug product as a function of timefollowing immersion in 0.06 N HCl aq dissolution media is carried outusing a USP Apparatus 2 (paddles). Samples of the drug product areperiodically withdrawn from the dissolution media and their dimensionsmeasured using calipers.

Drug Product Rigidity

Samples of the drug product are placed in a USP Apparatus 2 (paddles)containing 0.06 N HCl aq dissolution media. Samples of the drug productare periodically withdrawn and their rigidity measured using a textureanalyzer (TA 132) with the following settings: 5 kg load cell; TA-8¼″ball probe; 0.5 g trigger force; 0.2 mm/s test speed; 10 points/sacquisition rate; 10 mm distance.

Drug Product Stability

Stability testing is carried out by placing samples of the drug productin open HDPE bottles or induction-sealed HDPE bottles, which are storedat 40° C. and 75% relative humidity. Samples of the drug product arepulled at various time intervals—e.g., at 2 weeks for initial screeningand at 3 weeks, 6 weeks, or 3 months for subsequent testing—and analyzedfor pregabalin content (%, w/w) and lactam content (%, weight oflactam/initial weight of pregabalin) using HPLC.

Examples 1 to 11

TABLES 2 and 3 show compositions of laboratory-scale batches (25 g)containing pregabalin and various excipients; TABLES 4 and 5 showresults of drug release as a function of time. For each of theformulations, drug product was prepared by blending all of the tabletcomponents except for magnesium stearate in a TURBULA® mixer for about15 minutes. Magnesium stearate was passed through a #20 standard sieveand combined with the contents of the TURBULA® mixer using a spatula.The resulting coarse blend was subsequently mixed in the TURBULA® mixerfor an additional 4 minutes to obtain a final blend. Each of the finalblends was compacted in a CARVER® Press using a compression force of3000 pounds (EXAMPLES 1 to 5) or 2000 pounds (EXAMPLES 6 to 11) and adwell time of 0.1 min, resulting in tablets with average hardness valuesof about 30 kp and nominal tablet weights of 1 g and 1.125 g,respectively. For some of the formulations (EXAMPLES 1 to 5), pregabalinwas coated with COMPRITOL® 888 by high-shear granulation prior toblending with the other excipients.

Examples 12 to 14

TABLE 6 shows compositions of laboratory-scale batches (100 g) whichcontain pregabalin and excipients, and TABLE 7 shows drug release as afunction of time. For each of the compositions, drug product wasprepared by first combining pregabalin with COMPRITOL® 888 in anextruder-granulator. With the exception of magnesium stearate, theremaining tablet components were blended with the resulting pregabalingranules in a 1-pint V-blender for about 15 minutes. Magnesium stearatewas passed through a #20 standard sieve and was combined with thecontents of the V-blender using a spatula. The resulting coarse blendwas subsequently mixed in the V-blender for an additional 4 minutes toobtain a final blend. Each of the final blends was compressed using asimulated KORSCH® XL 400 press (i.e., PRESSTER® Compaction Simulator)employing an average compression force of about 21 kN and average dwelltime of 12 msec. The tablets displayed an average hardness of about 20kp and a nominal tablet weight of about 1 g.

Examples 15 to 23

TABLE 8 shows compositions of laboratory-scale batches which containpregabalin and excipients; TABLE 9 shows lactam formation as a functionof time. Each of the formulations was made using a process similar tothat described above in EXAMPLES 12 to 14.

Examples 24 to 30

TABLE 10 shows compositions of laboratory-scale batches (up to 4 kg)which contain pregabalin and excipients; TABLE 11 shows drug release asa function of time; TABLES 12 and 13 show tablet swelling and changes intablet rigidity following immersion in an aqueous solution; and TABLE 14shows lactam formation as a function of time. Drug products for some ofthe compositions (EXAMPLES 25 to 29) were made using processes similarto those described in EXAMPLES 12 to 14.

Drug product for EXAMPLE 24 was prepared by blending all of the tabletcomponents except magnesium stearate in a 16-quart V-blender for 15minutes. Magnesium stearate was passed through a #30 standard sieve andwas combined with the contents of the V-blender using a spatula. Theresulting coarse blend was subsequently mixed in the V-blender for anadditional 5 minutes to obtain a final blend. The final blend wascompressed in a MANESTY® Betapress using a diamond-shaped(quadrilateral) punch (0.6299″×0.748″, 0.0700″ cup depth, 0.0040″ land)and a triangle-shaped punch (0.6665″×0.6906″, 0.0600″ cup depth, 0.0040″land). For diamond-shaped tooling, an average tablet hardness of 8.6 kpwas obtained for 10 tablets at a pre-compression force setting of about2.1 kN and a lower main compression setting of about 36 kN. Fortriangle-shaped tooling, an average tablet hardness of 9.0 kp wasobtained for 10 tablets at a pre-compression force setting of about 2.2kN and a lower main compression setting of about 39.8 kN. The loss inweight upon friability testing was 0.3% for the diamond-shaped tabletsand 0.2% for the triangle-shaped tablets, respectively.

Tablets prepared using the MANESTY® Betapress (EXAMPLE 24) exhibitedsubstantially lower tablet hardness than those prepared in previousexamples. As a result, the magnesium stearate content of the compositionwas reduced from 1% to 0.5% to improve tablet hardness (EXAMPLE 30).Drug product was prepared in a manner similar to EXAMPLE 24, except thebatch size was reduced from 4 kg to 2 kg and the blending time followingmagnesium stearate addition was reduced to 4 minutes. The final blendwas compressed on the MANESTY® Betapress using the triangle tooling. Ata pre-compression force setting of 2.8 kN and lower main compressionforce setting of 41.5 kN, the tablets had an average (n=10) hardness of15.2 kp and exhibited 0% weight loss in friability testing. When thepre-compression force setting and the lower main compression forcesetting were changed to 3.1 kN and 33.2 kN, respectively, the tabletshad an average (n=10) hardness of 12.1 kp and exhibited a 0.07% weightloss in friability testing.

Example 31

TABLE 15 shows simulated steady-state minimum (C_(MIN)) and maximum(C_(MAX)) plasma concentrations of pregabalin, as well as time toC_(MAX) (t_(MAX)), for QD pharmaceutical compositions that contain 600mg of pregabalin. The compositions are retained in the stomach fort_(R)=3, 5, 8, or 10 hours and have total dissolution times t₁₀₀=6, 8,10, 12, or 16 hours. For comparison purposes, TABLE 15 also showssteady-state PK parameters for an IR pharmaceutical compositioncontaining 300 mg of pregabalin which is dosed twice daily.

The PK simulations are based on a QD dosage form having a normalizeddissolution profile provided in TABLE 16. In addition, the PK simulationshown in TABLE 15 assumes that (1) the pharmaceutical compositionremains in the stomach the specified time period (t_(R)) for eachsimulation; (2) the total effective absorption time (window) is 6hours—the average absorption window for the small intestine and theascending portion of the colon of the time in the stomach—plus t_(R);(3) the absorption rate in the lower portion of the small intestine issimilar to the upper portion; and (4) the effect of taking thepharmaceutical composition with food, at bedtime, or with food and atbedtime, has no effect on the absorption rate. Food has been shown todelay t_(MAX) of IR formulations, but does not appear to affect theextent of drug absorption. Sleep, however, will likely decrease the rateof drug absorption so that the simulations may underestimate the delayin t_(MAX).

As noted above, the results in TABLE 15 are based on an averageabsorption window associated with an IR formulation of 6 hours—PKprofiles of individual patients receiving the QD dosage could differ.Indeed, PK simulations for a QD dosage form containing 600 mg ofpregabalin and exhibiting a t₁₀₀ of 12 hours and a t_(R) of 5 hours andin which t_(R) varies from 3.4 hours to 7.7 hours suggests that a t₁₀₀(or t₉₀) approximately 4 to 6 hours longer than t_(R) reducesvariability among subjects.

Example 32

A single-dose pharmacokinetic study was performed to assess theperformance of the QD formulation of EXAMPLE 30. The QD dosage form wasgiven (1) in the fasted state, (2) following a high fat breakfast(morning treatment), and (3) following a high fat supper (eveningtreatment) in accordance with guidelines established by the U.S. Foodand Drug Administration. See, U.S. Department of Health and HumanServices, Food and Drug Administration, Center for Drug Evaluation andResearch, Guidance for Industry, Food-Effect Bioavailability and FedBioequivalence Studies (December 2002). Here, “high-fat” means thatapproximately 50 percent of the total caloric content of the meal wasderived from fat. The pharmacokinetic results of these three treatmentswere compared to the results obtained for an identical dose (300 mg) ofan immediate release formulation (capsule) comprised of pregabalin,lactose monohydrate, maize starch, and talc.

Based on pregabalin C_(MAX) and t_(MAX) values, peak exposure was lowerand occurred later for all three QD formulation treatments relative tothe IR capsule, indicating a slower rate of absorption from the QDformulation. Mean t_(MAX) for the QD formulation was about 4 hours forthe fasted treatment, more than 2-fold later than the mean t_(MAX) of1.5 hours for the IR capsule. Following administration of a high-fatmeal, t_(MAX) for the QD formulation increased to approximately 10 hours(9.7 hours for the morning treatment and 10.7 hours for eveningtreatment). Based on mean area under the plasma concentration-time curvefrom time zero to time infinity, total pregabalin exposure for the QDformulation fasted was less than half of that for the IR capsule.However, when the QD formulation was administered following a high-fatmeal, total pregabalin exposures for both the morning and eveningtreatments were similar to that from the IR capsule. The total exposureachieved when the QD formulation was administered after a high-fat mealwas bioequivalent to the IR formulation and should achieve an acceptableprofile for once daily dosing.

It should be noted that, as used in this specification and the appendedclaims, singular articles such as “a,” “an,” and “the,” may refer to oneobject or to a plurality of objects unless the context clearly indicatesotherwise. Thus, for example, reference to a composition containing “acompound” may include a single compound or two or more compounds.

It is to be understood that the above description is intended to beillustrative and not restrictive. Many embodiments will be apparent tothose of skill in the art upon reading the above description. The scopeof the invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled. The disclosures of all articles and references,including patents, patent applications and publications, areincorporated herein by reference in their entirety and for all purposes.

TABLE 2 Pharmaceutical compositions containing pregabalin (% w/w) -EXAMPLES 1 to 5 Component 1 2 3 4 5 Pregabalin 30.0 30.0 30.0 30.0 30.0KOLLIDON ® SR 31.7 31.7 31.7 41.7 41.7 PLASDONE ® XL 15.0 15.0 15.0 15.015.0 GELCARIN ® GP812 15.0 5.0 GELCARIN ® GP911 15.0 VISCARIN ® GP10915.0 5.0 COMPRITOL ® 888 7.8 7.8 7.8 7.8 7.8 Magnesium stearate 0.5 0.50.5 0.5 0.5 Total 100.0 100.0 100.0 100.0 100.0

TABLE 3 Pharmaceutical compositions containing pregabalin (%w/w)-EXAMPLES 6 to 11 Component 6 7 8 9 10 11 Pregabalin 26.7 26.7 26.726.7 26.7 26.7 KOLLIDON ® SR 40.0 40.0 30.0 30.0 37.3 30.0 PLASDONE ® XL20.0 25.0 20.0 25.0 25.0 28.0 POLYOX ® WSR Coagulant 12.3 7.3 22.3 17.310.0 14.3 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 Total 100.0 100.0100.0 100.0 100.0 100.0

TABLE 4 Pregabalin release (% w/w) as a function of time (hours) -EXAMPLES 1 to 5 Time 1 2 3 4 5 0.0 0.0 0.0 0.0 0.0 0.0 0.5 16.7 15.010.8 51.6 39.0 2.0 35.5 31.4 26.1 84.0 63.5 4.0 48.4 43.2 39.1 96.8 76.66.0 56.8 52.1 48.9 101.0 85.0 9.0 66.9 63.2 60.5 101.4 92.8 12.0 75.772.9 69.6 101.4 98.0 Measurements carried out at 37° C. using a USP 3apparatus containing 0.06N HCl aq. Each of the release data for Examples1-3 is an average of two samples; release data for Examples 4 and 5 arefor single samples.

TABLE 5 Pregabalin release (% w/w) as a function of time(hours)-EXAMPLES 6 to 11 Time 6 7 8 9 10 11 0.0 0.0 0.0 0.0 0.0 0.0 0.00.5 17.4 31.1 13.2 15.8 16.4 20.6 1.0 25.7 43.7 27.2 32.6 35.6 43.1 2.036.0 58.1 4.0 50.5 74.8 40.9 47.4 50.9 59.5 6.0 52.6 59.4 62.6 70.3 8.070.1 92.3 9.0 66.9 73.6 76.0 82.0 12.0 83.0 101.4 78.7 84.5 85.5 90.316.0 91.8 107.2 20.0 98.5 109.2 24.0 103.4 109.2 Measurements carriedout at 37° C. using a USP 3 apparatus containing 0.05 M aq acetatebuffer (pH 4.5). Each of the release data for Examples 8-11 is anaverage of 2 samples; release data for Examples 6 and 7 are for singlesamples.

TABLE 6 Pharmaceutical compositions containing pregabalin (% w/w) -EXAMPLES 12 to 14 Component 12 13 14 Pregabalin 30.0 30.0 30.0KOLLIDON ® SR 51.7 49.7 46.7 PLASDONE ® XL 10.0 12.0 15.0 COMPRITOL ®888 7.8 7.8 7.8 Magnesium stearate 0.5 0.5 0.5 Total 100.0 100.0 100.0

TABLE 7 Pregabalin release (% w/w) as a function of time (hours) -EXAMPLES 12 to 14 Time 12 13 14 0.0 0.0 0.0 0.0 0.5 42.2 34.7 47.0 2.067.5 58.2 88.9 4.0 82.8 75.1 105.2 6.0 91.5 86.2 111.9 9.0 98.8 96.1112.9 12.0 101.8 102.2 112.9 Measurements carried out at 37° C. using aUSP 3 apparatus containing 0.06N HCl aq. Each of the release data forExamples 12-14 is an average of 2 samples.

TABLE 8 Pharmaceutical compositions containing pregabalin (%w/w)-EXAMPLES 15 to 23 Component 15 16 17 18 19 20 21 22 23 Pregabalin30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 30.0 KOLLIDON ® SR 22.0 34.542.0 27.0 39.5 50.0 61.5 45.0 29.5 PLASDONE ® XL 20.0 17.5 10.0 20.015.0 12.0 8.0 12.0 15.0 POLYOX ® WSR Coagulant 20.0 17.5 CARBOPOL ® 71G5.0 VISCARIN ® GP109 15.0 15.0 NATROSOL ® 250 17.5 17.5 COMPRITOL ® 8887.5 7.5 7.5 7.5 7.5 Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.50.5 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

TABLE 9 Lactam formation (%, weight of lactam/initial weight ofpregabalin) Example Intitial 2 Weeks 15 0.005 0.008 16 0.006 0.007 170.011 0.012 18 0.009 0.011 19 0.015 0.033 20 0.099 0.010 21 0.016 0.01122 0.012 0.018 23 0.010 0.014 All samples stored in open bottles at 40°C. and 75% RH except for Example 19, which was stored in a closedbottle.

TABLE 10 Pharmaceutical compositions containing pregabalin (%w/w)-EXAMPLES 24 to 30 Component 24 25 26 27 28 29 30 Pregabalin 26.726.7 26.7 26.7 26.7 26.7 26.7 KOLLIDON ® SR 22.3 22.3 19.3 9.3 25.3 22.8PLASDONE ® XL 25.0 25.0 25.0 25.0 23.5 25.0 POLYOX ® WSR 20.0 20.0 N60KNF POLYOX ® WSR 10.0 10.0 10.0 23.5 Coagulant POLYOX ® WSR 51.7 303CARBOPOL ® 71G 5.0 5.0 HEC 250 HHX 15.0 18.0 18.0 METHOCEL ® 14.5 K15MMETHOCEL ® E5 6.1 Mannitol 10.0 Magnesium 1.0 1.0 1.0 1.0 1.0 1.0 0.5stearate Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0

TABLE 11 Pregabalin release (% w/w) as a function of time(hours)-EXAMPLES 24 to 30 Time 24 25 26 27 28 29 30 0 0.0 0.0 0.0 0.00.0 0.0 0.0 1 18.6 22.1 21.3 22.5 18.1 9.3 18.4 2 29.5 31.7 31.0 32.827.3 16.8 28.6 4 43.9 45.7 45.0 47.3 41.9 29.2 44.0 6 55.6 55.1 55.559.7 54.2 39.4 55.8 8 64.5 52.2 9 70.7 69.3 68.6 73.9 69.1 10 73.2 56.912 82.3 78.0 78.4 84.5 80.8 64.5 79.6 16 92.8 88.2 88.6 94.7 90.2 20102.7 96.2 24 106.8 99.3 99.0 103.6 100.4 Measurements carried out at37° C. using a USP 2 apparatus containing 0.06 N HCl aq.

TABLE 12 Tablet dimensions (L, H, W in mm) and volume (V in mm³) as afunction of time (hours)-EXAMPLES 24 & 30 24 30 Time L W H V L W H V 019.19 10.93 7.80 1637.23 17.10 17.70 6.71 1014.86 2 21.06 12.06 11.422901.99 19.80 20.14 10.42 2077.80 4 22.59 13.54 12.55 3837.94 20.7820.92 10.66 2318.58 6 22.80 13.18 12.97 3896.89 21.43 21.34 11.592648.90 9 23.93 13.93 13.84 4616.32 17.10 17.70 6.71 1014.86

TABLE 13 Rigidity (g · mm) as a function of time (hours)-EXAMPLES 24 &30 Time 24 30 0 2 4446.84 4 3004.47 1902.92 6 1759.25 1131.43 9 1129.57

TABLE 14 Pregabalin (% w/w) and corresponding lactam content (% based onweight of pregabalin) as a function of time-EXAMPLES 25 to 30 Time 25 30Initial 0.00 0.01 3 weeks 0.03 0.02 6 weeks 0.01 0.03 3 months 0.06 0.09

TABLE 15 Simulated steady-state PK parameters for IR and QD dosage formscontaining pregabalin t_(R) t₁₀₀ C_(MAX) C_(MIN) ¹ t_(MAX) ² hours hoursμg/mL μg/mL hours IR Dosage Form³ — — 8.85 2.80 0.75 QD Dosage Forms⁴ 36 9.73 1.48 6.0 3 8 8.76 1.62 8.0 3 10 7.67 1.57 9.0 3 12 6.77 1.38 9.03 16 5.81 1.18 9.0 5 6 9.73 1.48 6.0 5 8 8.76 1.62 8.0 5 10 7.89 1.7910.0 5 12 6.93 1.75 8.0 5 16 5.92 1.44 8.4 8 6 9.73 1.48 6.0 8 8 8.761.62 8.0 8 10 7.89 1.79 10.0 8 12 7.12 1.98 12.0 8 16 6.14 1.97 8.4 10 69.73 1.48 6.0 10 8 8.76 1.62 8.0 10 10 7.89 1.79 10.0 10 12 7.12 1.9812.0 10 16 6.34 2.45 8.4 ¹C_(MIN) occurs just prior to theadministration of the next dosage (i.e., at 12 and 24 hours postadministration for BID and QD dosage forms, respectively). ²Timefollowing administration of latest dosage. ³IR formulation containing300 mg of pregabalin, dosed twice daily. ⁴QD formulation containing 600mg of pregabalin.

TABLE 16 Amount of pregabalin released from dosage form as a function oftime (normalized) Time/t₁₀₀ % w/w dissolved 0.0 0 0.0658 21 0.132 320.263 47 0.526 68 0.789 85 1.0 100

1. (canceled)
 2. The pharmaceutical composition according to claim 16,wherein the pharmaceutical composition expands to a size of about 9 mmor greater when contacting water.
 3. The pharmaceutical compositionaccording to claim 16, wherein the pharmaceutical composition isretained in the stomach of a subject following oral dosing for about 3hours to about 14 hours.
 4. The pharmaceutical composition according toclaim 16, wherein the active pharmaceutical ingredient is released overa period of time that is about 4 hours to about 6 hours longer than thetime the pharmaceutical composition is retained in the stomach of asubject following oral dosing.
 5. The pharmaceutical compositionaccording to claim 16, wherein the active pharmaceutical ingredient isreleased over a period of time of about 12 hours to about 20 hours. 6.The pharmaceutical composition according to claim 16, in which theactive pharmaceutical ingredient exhibits an in vivo steady-stateC_(MAX) of about 9 μg/mL or less, or an in vivo steady-state C_(MIN) ofabout 0.7 μg/mL or greater, or an in vivo steady-state C_(MAX) of about9 μg/mL or less and an in vivo steady-state C_(MIN) of about 0.7 μg/mLor greater.
 7. (canceled)
 8. The pharmaceutical composition according toclaim 16, wherein the pharmaceutical composition is bioequivalent to animmediate release formulation comprising pregabalin, lactosemonohydrate, maize starch, and talc.
 9. A method of treating a conditionor disorder in a subject which is responsive to pregabalin, the methodcomprising administering to the subject a pharmaceutical composition asin claim 16, wherein the pharmaceutical composition is administeredorally once daily.
 10. The method according to claim 9, wherein thecondition or disorder is selected from epilepsy, pain, diabeticperipheral neuropathy, postherpetic neuralgia, physiological conditionsassociated with psychomotor stimulants, inflammation, gastrointestinaldamage, alcoholism, insomnia, fibromyalgia, anxiety, depression, mania,and bipolar disorder.
 11. A method of treating a condition or disorderin a subject which is responsive to pregabalin, the method comprisingadministering to the subject once daily a pharmaceutical compositioncomprising an active pharmaceutical ingredient and excipients, theactive pharmaceutical ingredient comprising pregabalin, or apharmaceutically acceptable complex, salt, solvate or hydrate thereof,and the excipients comprising a matrix forming agent and a swellingagent.
 12. The method according to claim 11, wherein the condition ordisorder is selected from epilepsy, pain, diabetic peripheralneuropathy, postherpetic neuralgia, physiological conditions associatedwith psychomotor stimulants, inflammation, gastrointestinal damage,alcoholism, insomnia, fibromyalgia, anxiety, depression, mania, andbipolar disorder.
 13. The method according to claim 11, in which theactive pharmaceutical ingredient exhibits an in vivo steady-stateC_(MAX) of about 9 μg/mL or less.
 14. The method according to claim 11,in which the active pharmaceutical ingredient exhibits an in vivosteady-state C_(MIN) of about 0.7 μg/mL or greater.
 15. The methodaccording to claim 11, in which the active pharmaceutical ingredientexhibits an in vivo steady-state C_(MAX) of about 9 μg/mL or less and anin vivo steady-state C_(MIN) of about 0.7 μg/mL or greater.
 16. Apharmaceutical composition comprising an active pharmaceuticalingredient and excipients, the active pharmaceutical ingredientcomprising pregabalin, or a pharmaceutically acceptable complex, salt,solvate or hydrate thereof, and the excipients comprising a matrixforming agent and a swelling agent, the matrix forming agent comprisingpolyvinyl acetate and polyvinylpyrrolidone, and the swelling agentcomprising cross-linked polyvinylpyrrolidone and polyethylene oxide,wherein the pharmaceutical composition is adapted for once-daily oraldosing; wherein the pregabalin comprises from about 5% to about 60% ofthe pharmaceutical composition by weight; the matrix forming agentcomprises from about 5% to about 45% of the pharmaceutical compositionby weight, and the swelling agent comprises from about 15% to about 70%of the pharmaceutical composition by weight.